Method of treatment

ABSTRACT

One embodiment of the invention provides a method for administering tasimelteon to a human patient that comprises orally administering an effective dose of tasimelteon under fasted conditions. Fasted conditions may comprise administering the tasimelteon without food, no food at least ½ hour prior to administration, no food at least 1 hour prior to administration, no food at least 1½ hours prior to administration, no food at least 2 hours prior to administration, no food at least 2½ hours prior to administration, or no food at least 3 hours prior to administration. According to such embodiments, tasimelteon may be administered, for example, at a dose of 20 mg/d. Tasimelteon may be administered where, for example, the patient is being treated for a circadian rhythm disorder or for a sleep disorder, including, for example, Non-24 Disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of co-pending U.S. ProvisionalApplication Ser. Nos. 61/903,354, filed 12 Nov. 2013 and 61/927,465,filed 14 Jan. 2014, which is hereby incorporated herein for all that itcontains as though fully set forth.

BACKGROUND OF THE INVENTION

Tasimelteon, and methods of using and processes for making tasimelteon,are disclosed in various references, including U.S. Pat. No. 5,856,529,U.S. patent application Publication No. 20090105333, and U.S. patentapplication Publication No. 20130197076, copies of which are appendedhereto and are incorporated herein by reference as though fully setforth.

SUMMARY

One embodiment of the invention provides a method for administeringtasimelteon to a human patient that comprises orally administering aneffective dose of tasimelteon under fasted conditions. Fasted conditionsmay comprise administering the tasimelteon without food, no food atleast ½ hour prior to administration, no food at least 1 hour prior toadministration, no food at least 1½ hours prior to administration, nofood at least 2 hours prior to administration, no food at least 2½ hoursprior to administration, or no food at least 3 hours prior toadministration. According to such embodiments, tasimelteon may beadministered, for example, at a dose of 20 mg/d. Tasimelteon may beadministered where, for example, the patient is being treated for acircadian rhythm disorder or for a sleep disorder, including, forexample, Non-24 Disorder.

Another embodiment of the invention provides a method for administeringtasimelteon to a human patient that comprises instructing the patientthat tasimelteon should be taken without food.

Still another embodiment of the invention provides a method forshortening T_(max) in a human patient being treated with tasimelteon,said method comprising orally administering an effective dose oftasimelteon under fasted conditions.

In still yet another embodiment, the invention provides a method ofmarketing or selling tasimelteon that comprises informing prescribers,patients, and/or insurers that tasimelteon should be taken under fastedconditions, such as by including such instructions in printedprescribing information that is packaged with a container comprisingtasimelteon capsules.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features of this invention will be more readilyunderstood from the following detailed description of the variousaspects of the invention taken in conjunction with the accompanyingdrawings that depict various embodiments of the invention, in which:

FIG. 1 shows a flow diagram of a study related to the invention.

It is noted that the drawings of the invention are not to scale. Thedrawings are intended to depict only typical aspects of the invention,and therefore should not be considered as limiting the scope of theinvention.

DESCRIPTION OF THE INVENTION

This invention relates to administration of tasimelteon under fastedconditions, i.e., without food.

A clinical study was undertaken to investigate the effects of food onadministration of tasimelteon. Specifically, the primary objective ofthe study was to investigate the influence of food(high-calorie/high-fat) on the pharmacokinetics of 100 mg of tasimelteonin healthy subjects. This was a single-center, open-label, crossoverdesign which lasted up to 5 weeks. 26 Healthy male and female subjects(18-50 years old) were enrolled in the study. There was a 2-period,randomized, 2-sequence crossover design where each subject received 100mg tasimelteon either with or without food. Subjects were randomlyassigned to receive a 100 mg tasimelteon capsule under fasted conditionsor a 100 mg tasimelteon capsule under fed conditions (i.e., 30 minutesafter beginning to ingest a high-fat meal). There was a 7-day washoutbetween treatment groups. FIG. 1 depicts an example of the overall studydesign. In FIG. 1, tasimelteon is referred to as VEC-162.

For purposes of the study depicted in FIG. 1, administration underfasted conditions was administration with 240 mL of water atapproximately 6:00 AM, after at least a 10-hour fast. Subjects were notallowed to eat any food for at least 4 hours postdose. Subjects wereallowed to drink water as desired except 1 hour before and 2 hours afterdrug administration.

Administration under fed conditions was administration with 240 mL ofwater at approximately 6:00 AM, after a high-fat/high=calorie breakfast,which included one cup of milk. Subjects began the recommended meal 30minutes prior to drug administration. Subjects finished eating the mealin 30 minutes or less and the drug was administered approximately 30minutes after the start of the meal. Subjects were not allowed to eatany food for at least 4 hours postdose. Subjects were allowed to drinkwater as desired except 1 hour before and 2 hours after drugadministration.

25 Subjects completed both periods of the study. Administration oftasimelteon with a high-fat/high-calorie meal resulted in a lowerC_(max) and longer T_(max). The mean C_(max) of 786+/−432 ng/mL underfasted conditions was reduced to a mean C_(max) of 445+/−255 ng/mL witha geometric mean ratio of 55.82% and an associated 90% confidenceinterval of 49.72% to 62.67%. The extent of absorption, as measured byAUC_((0-t)) and AUC_((Inf)) was comparable under both fed and fastedconditions with geometric mean ratios of 108.57% and 106.54%,respectively, and 90% confidence intervals contained within the 80% to125% equivalence window. Consistent with a descrease in C_(max) and nochange in AUC, i.e., a decrease in the rate but not the extent ofabsorption, the median T_(max) increased from 0.75 hours under fastedconditions to 2.5 hours under fed conditions.

From this study, it was concluded that administration of tasimelteonwith a high-fat/high calorie meal results in a significant decrease inthe rate of absorption but no significant change in the extent ofabsorption.

Thus, in illustrative embodiments, the invention comprises:

a method for administering tasimelteon to a human patient that comprisesorally administering an effective dose of tasimelteon under fastedconditions;

a method for administering tasimelteon to a human patient that comprisesinstructing the patient that tasimelteon should be taken without food;

a method for shortening T_(max) in a human patient being treated withtasimelteon, said method comprising orally administering an effectivedose of tasimelteon under fasted conditions;

a method of marketing or selling tasimelteon that comprises informingprescribers, patients, and/or insurers that tasimelteon should be takenunder fasted conditions, such as by including such instructions inprinted prescribing information that is packaged with a containercomprising tasimelteon capsules.

In specific illustrative embodiments, the fasted conditions comprisesadministering the tasimelteon without food;

the fasted conditions comprises no food at least ½ hour prior toadministration; the fasted conditions comprises no food at least 1 hourprior to administration; the fasted conditions comprises no food atleast 1½ hours prior to administration;

the fasted conditions comprises no food at least 2 hours prior toadministration; the fasted conditions comprises no food at least 2½hours prior to administration; or

the fasted conditions comprises no food at least 3 hours prior toadministration;

In other illustrative embodiments, the Cmax is lowered while AUC isapproximately the same whether the drug is administered under fedconditions or under fasted conditions;

the dose of tasimelteon is 20 mg/d;

the patient is being treated for a circadian rhythm disorder or for asleep disorder; and/or

the patient is being treated for Non-24 Disorder.

Specific illustrative language for inclusion in the prescribinginformation (i.e., the “label”) might include, e.g.:

“The peak concentration (T_(max)) of tasimelteon occurred atapproximately 0.5 to 3 hours after fasted oral administration.

-   When administered with a high-fat meal, the C_(max) of tasimelteon    was 44% lower than when given in a fasted state, and the median    T_(max) was delayed by approximately 1.75 hours. Therefore, HETLIOZ    should be taken without food.”

Tasimelteon is useful in a method of entraining a patient suffering froman abnormal melatonin circadian rhythm, or an abnormal cortisolcircadian rhythm, to a 24 hour circadian rhythm by internallyadministering to the patient an effective amount thereof. Anillustrative embodiment is a method of entraining a patient sufferingfrom Non-24 to a 24hour sleep-wake cycle in which the patient awakens ator near a target wake time following a daily sleep period, e.g.approximately 7 to 9 hours (understanding, of course, that the patientmay not actually sleep during the entire sleep period), said methodcomprising: treating the patient by internally administering to thepatient an effective amount of tasimelteon.

In general, the tasimelteon, is administered in a pharmaceuticalformulation q.d. prior to the start of the target sleep time. It hasbeen found that in treating Non-24, it is not necessary to administerthe drug more than about 1 hour prior to the start of the target sleeptime such that the drug can be administered, e.g., at about 0.5 to about1.5 hours prior to sleep time.

What is claimed is:
 1. A method of treating a human patient sufferingfrom a circadian rhythm disorder or a sleep disorder that comprisesorally administering to the patient an effective dose of tasimelteonwithout food, wherein the effective dose is 20 mg/d.
 2. The method ofclaim 1, wherein the tasimelteon is administered with no food after atleast ½ hour prior to administration.
 3. The method of claim 1, whereinC_(max) of the tasimelteon is lowered while AUC is approximately thesame whether the tasimelteon is administered under fed conditions orunder fasted conditions.
 4. The method of claim 1, wherein the patientis suffering from a circadian rhythm disorder.
 5. The method of claim 4,wherein the circadian rhythm disorder is Non-24 Disorder.
 6. The methodfor shortening T_(max) in a human patient suffering from a circadianrhythm disorder or a sleep disorder and being treated with tasimelteon,said method comprising orally administering an effective dose oftasimelteon without food, wherein the effective dose is 20 mg/d.
 7. Themethod of claim 6, wherein the tasimelteon is administered with no foodafter at least ½ hour prior to administration.
 8. The method of claim 6,wherein C_(max) of the tasimelteon is lowered while AUC is approximatelythe same whether the tasimelteon is administered under fed conditions orunder fasted conditions.
 9. The method of claim 6, wherein the patientis suffering from a circadian rhythm disorder.
 10. The method of claim9, wherein the circadian rhythm disorder is Non-24 Disorder.
 11. Themethod of claim 1, wherein the tasimelteon is administered with no foodafter at least one hour prior to administration.
 12. The method of claim1, wherein the tasimelteon is administered with no food after at leastone-and-one-half hours prior to administration.
 13. The method of claim1, wherein the tasimelteon is administered with no food after at leasttwo hours prior to administration.
 14. The method of claim 1, whereinthe tasimelteon is administered with no food after at leasttwo-and-one-half hours prior to administration.
 15. The method of claim1, wherein the tasimelteon is administered with no food after at leastthree hours prior to administration.
 16. The method of claim 6, whereinthe tasimelteon is administered with no food after at least one hourprior to administration.
 17. The method of claim 6, wherein thetasimelteon is administered with no food after at least one-and-one-halfhours prior to administration.
 18. The method of claim 6, wherein thetasimelteon is administered with no food after at least two hours priorto administration.
 19. The method of claim 6, wherein the tasimelteon isadministered with no food after at least two-and-one-half hours prior toadministration.
 20. The method of claim 6, wherein the tasimelteon isadministered with no food after at least three hours prior toadministration.